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Due the their high antioxidant properties and other function, many astaxanthin containing

nutraceuticals with potent effect on human health are coming onto the market

STRUCTURE AND SOURCE OF ASTAXANTHIN

The astaxanthin molecule has a symmetric configuration and two chiral centers ; two carbon

atoms adjacent to hydroxyl functional group are chiral. There are three enantiometric isomer of

astaxanthin, 3S 3S, 3R 3R, and 3R 3S. chemically synthesized astaxanthin is a mixture of

1:2:1 of 3s 3s 3r 3r and 3r 3r enantiomer, respectively. This is mainly used in the field of

aquaculture as a reviver and is not used as an ingredient in human neutraceuticals. A green

microalga ( H. pluvialis), a red yeast (phaffia rhodozyma), and crustacean by product are

commercially available as natural sources of the astaxanthin pigment. These sources are often

used in the nutraceutical industry because of recent natural food trends and safety concerns. The

form of astaxanthin in these natural sources are slightly different from each other. Astaxanthinfrom haematococcus is the 3s 3s isomer and is almost esterified with fatty acid to form mono or

diester. In contrast, phaffia rhodozyma is reported to synthesize the 3R, 3Risomer, which is

mainly unesterified. Haematococcus alga is considered to be the most efficient natural source of

astaxanthin and is presently used as the main source of natural astaxanthin.

ANTIOXIDATIVE ACTIVITY OF ASTAXANTHIN

Carotenoids are generally known to possess powerful antioxidative activity, thought to be

because of their long conjugated polyene system. The stable structure and strong antioxidative

activity of astaxanthin is considered to be due to the conjugation of the oxo group to the polyene

system. Astaxanthin is reported to show a strong quenching effect against singlet oxygen, with

potency more than 100-fold higher than that of a-tocopherol. This same study also reports that

astaxanthin shows strong activity against lipid peroxidation. In addition, astaxanthin is reported

to have no pro-oxidative properties; other carotenoids, such as b-catorene, lycopene, and

zeaxanthin, under certain conditions, are considered to possess pro-oxidative properties.

HEMATOCOCCUS ALGAE

H. pluvialis, Flotow, Volvocales, Chlorophyceae, is a unicellular freshwater green microalgae. In

response to environmental condition, the green flagellated cells (vegetative cells) gradually

transform into cyst cells without flagellae ( the aplanospores), accompanied by a markedaccumulation of astaxanthin, resulting in the formation of red-colored cells. The size of

vegetative cell is less than 10micrometer in diameter, although is gradually increases to over 40-

50 nm after transforming into cist cells. In oxygenic photosynthetic organisms, carotenoids play

importany roles in the light-harvesting complex and in the protection of photosynthetic

machinery, by dissipating axcess light energy. These types of carotenoids are referred to as

primary carotenoids and are essential in metabolism. These carotenoids are localized in thylakoid

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membranes of rge chloroplast. In contrast, secondary carotenoids such as astaxanthin are not

functionally obligatory for photosynthesis. Astaxanthin in H. pluvialis accumulates in

cytoplasmic lipid globules of the cells: accumulation occurs in response to environmental

stimuli, such as high light intensity and oligotrophic conditions. In H.pluvialis, it is considered

that astaxanthin acts as sunshade , to provide protection from photodamage, or to minimize

oxidation of storage lipids.

BENEFITS OF ASTAXANTHIN FOR HUMAN HEALTH MANAGEMENT

As a company which supplies functional food ingredients, it is important that we invedtigate the

effectiveness of the ingredient we produce. It is generally accepted that oxidative stress is

involved not only in the normal aging process but also in the pathogenesis of many acute,

chronic, and agerelated diseases, including inflammation, cancer, cardiovascular disease,

neurodegenetarive disease, lung disease, and eye disease. Naturals antioxidants are scavengers of

reactive oxygen species including free radicals, and therefore have broad implications in

antiaging and human health management. As described in the previous section, astaxanthin has astrong antioxidative activity and hence various physiological efficacies. In the next section, we

present out clinica evidence for the efficacy of our astaxanthin-rich H.pluvialis oil on oxidative

stress-related diseases/aging, especially atopic dermatitis, brain health, and metabolic syndrome.

ASTAXANTHIN AND ATOPIC DERMATITIS

There are many lines of evidence suggesting that allergic disorders, such as atopic dermatitis,

asthma, and rhinitis, are mediated by oxidative stress. We observed that the administration of

astaxanthin significantly suppressed ear swelling in NC/Nga mice which had been previously

sensitized by intradermal injections of mite antigen into the ear pinnae, inducing atopicdermatitis like lesions. We further investigated the effect of astaxanthin intake on atopic

dermatitis by a double-blind, randomized, placebo-controlled clinical trial.

In this study, patients (aged 19-51 years) with mild to moderate atopic dermatitis ingested

astaxanthin-rich H.pluvialis oil, equivalent to 12 mg of astaxanthin dialcohol (Ax group, six men

and eight woman) or corn oil (placebo group , six men and seven women) contained of soft

capsules, once daily for 4 weeks. Before and after administration, evaluations were made on

severity (scoring atopic dermatitis, SCORAD), pruritus (visual analog scale; VAS), quality of

life (Skindex-16 and state trait anxiety inventory, STAI), immune function (Th1/Th2 and blood

catecholamines), and antioxidative status (urine 8-OHdG and isoprostane). No significantdifference in severity and pruritus was apparent between the Ax and placebo groups. However,

the Ax group showed significant amelioration of symptoms evaluated by skindex-16 and on

anxiety state evaluated by STAI. The ameliorating effect on anxiety by astaxanthin was

supported by the level of the stress hormone, dopamine, which was significantly decreased in the

Ax group. The level of urine 8-OHdG,which is reported to be high in patient with atopic

dermatitis, decreased significantly in the Ax group, indicating that astaxanthin intake has an

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antioxidative efficacy. Furthermore, the study revealed that there was a statistically significant

shift in the Th1/Th2 balance toward Th1 in the Ax group. Atopic dermatitis is characterized by

Th2-dominated allergic skin inflammation. It is known that higher anxiety in patients enhances

the Th2-type response, due to dysregulation of the neuro immune system, leading to worsening

of the allergic symptoms. The finding of this study, which showed that patients in the Ax group

showed reduced anxiety accompanied by a shift in the Th1/Th2 balance toward Th1, strongly

suggests that astaxanthin is a promising food factor in the management of atopic dermatitis.

ASTAXANTHIN AND BRAIN HEALTH

Brain aging, either natural or in neurodegenerative disorders, is also closely associated with

oxsidative stress, subsenquent damage to cellular components (DNA oxidation/mutation, protein

modification/aggregation, and lipid peroxidation), inflammation, and other factors, including

excess calorie intake, insulin resistance, and mitochondrial dysfunction leading to neuron death.

In connection with the effect to astaxanthin on the factors involved in brain aging, we have

observed the following findings; 1. Astaxanthin protects neuroblastoma cells from oxidative-stress induced apoptosis in vitro. 2. In dopaminergic neuron-specific manganese superoxide

dismutase (MnSOD)-deficient mice which display parkinsonian symptons, oral administration of

astaxanthin resulted in improvement of body weight loss and behavior function and hence an

increase in life span. 3. Astaxanthin improves mitochondrial function by maintaining a high

mitochondrial membrane potential, stimulating respiration , maintaining mitochondria in a

reduced state even under oxidative challenge. In addition, a memory improving effect of

astaxanthin in mice has been reported by other research groups. However, there had been no

studies investigating the effect of astaxanthin on the higher cognitive function of the human

brain.

We therefore conducted a preliminary clinical evaluation, an open-label trial using 10 otherwise

healthy male subjects (50-69 years of age) who complained of age related forgetfulness. Age

associated memory impairment is a common condition characterized by very mild symptoms of

cognitive decline that occur as part of the normal aging process (NYU medical center / NYU

school of medicine) in our study, subject ingested astaxanthin-rich H.pluvialis oil, equivalent to

12 mg of astaxanthin dialcohol, contained in soft capsules, once daily for 12 weeks. Cognitive

function was evaluated before administration (at baseline) and again every six weeks during the

study, using either the CogHealth tool (Cogstage, Melbourne, Australia) or the event-related

P300 recognition response elicited by an auditory task. Coghealth is a cognitive function test

specifically designed to detect changes in healthy or mildly impaired subjects at an early date.

The trial revealed significant reduction in response time on all tasks in Coghealth ; phychomotor

speed, impulse control, working memory, episodic learning, and attention, after 12 weeks intake

of astaxanthin. The accuracy on the working memory task in coghealth was also significantly

improved after 12 weeks of treatment. The P300 peak amplitude tended to increase after 12

weeks astaxanthin administration, indicating that astaxanthin might increase patient informasion

processing capacity and selective attention. All tasks investigationby coghealth and P300 are

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indispensable for a skilful performance in daily like activities such as driving, which is a

complex form of activity involving specific cognitive and phychomotor functions. Age-related

decreases in these task are therefore a serious problem, causing an increased number of traffic

accident and deaths in older people. double-blind, randomized, placebo-controlled clinical trial

investigation the effect of astaxanthin on coghealth tasks and driving performance are currently

in progress.

ASTAXANTHIN AND METABOLIC SYNDROME

Metabolic syndrome is characterized by a clustering of metabolic risk factors for cardiovascular

disease in one person. The risk factors include abdominal obesity; insulin resistance, elevated

blood glucose, atherogenic dysplidemia and hypertension. Metabolic syndrome is closely

associated with oxidative stress and adipose tissue inflammation, and the improving effects of

astaxanthin on metabolic syndrome have been suggested in several animal models.

We attemted to confirm the clinical efficacy of astaxanthin in an open label uncontrolled studyusing volunteers at risk of metabolic syndrome. In this trial, a total of 17 volunteers between 12

and 65 years of age (13 men and 4 women) at risk of developing metabolic syndrome were

administered with astaxanthin-rich H.pluvialis oil, equivalent to 8 mg of astaxanthin dialcohol,

twice daily for 12 weeks. A significant increase in adiponectin levels and a significant decrease

in tumor necrosis factors (TNF) a levels were onserved. In addition, a significant decrease in

glycohemoglobin (HbAIc), a diagnostic marked of diabetes, was observed. Adiponectin has an

antidiabetic effect; it decreaed blood glucose as a good indicator of metabolic syndrome. While

TNF-a increases insulin resistance. It is generally accepted that the reduced secretion of

adiponectin and increased secretion of TNF-a in dysfunctional adipose tissue (inflamed adipose

with enlarged adipocytes and impaired preadipocyte differentiation) increase insulin resistance inthe phatogenesis of metabolic syndrome. Our result showed that astaxanthin intake increased

adiponectin levels and decreased TNF-a levels, which strongly suggest that astaxanthin has a

positive effect on the proin flammatory state of dysfunctional adipose tissue and hence on

elevated blood glucose. This is confirmed by a significant decrease in glycohemoglobin (HbAIc)

in humans at risk of metabolic syndrome.

CONCLUDING REMARKS

In this chapter, we discussed our indoor photobioreactor, a highly controlled microalgal

cultivation technology, with high sterility, light illumination efficiency, and therefore high and

stable biomass productivity on a commercial scale. Although microalgae have been recognized

as promising organism to provide sourced of natural product in functional foods in the

nutraceutical and pharmaceutical industry, only a few algal strains and their products have been

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successfully marketed so far, as described in section 18.2. our microalgal cultivation technology,

using an indoor photobioreactor, is considered to be competitive in the production of high-value

bioactive metabolites with low cellular content. The use of sterilized, high density algal

suspensions can be advantageous in downstream processing such as concentration and extraction

processes, particularly for neutraceticals and pharmaceuticals obtained from microalgae which

are difficult to culture outdoors. Another possible application of our technology seems to be the

cultivation of genetically engineered microalgae that will most likely be banned from outdoor

cultivation systems, transgenic algal strains that express good concentrations of several

recombinant therapeutic proteins have already been successfully generated. Further improvement

of our cultivation technology, as well as innovations of other important technologies such as

solar electricity and low-cost reactor materials, are needed to develop more competitive and

economically feasible algal biomass production systems. Together with finding useful algal

strains and their metabolites, he innovations of our cultivation technology and other cultivation-

related technologies will bring advancement and expansion to microalgal business opportunities

in the human health industry.